1. Field Of The Invention
The invention relates to a new process for the production of (+) biotin.
2. Background Art
(+) Biotin is a human vitamin which is known as vitamin H. But (+) biotin is also used as a pharmaceutical agent for the treatment of dermatosis and as a feed additive with growth-increasing action for domestic animals.
Various processes have been described in the prior art for the production of (+) biotin.
A process is known from U.S. Pat. No. 2,489,232 according to which racemic biotin is produced. But since, as is known, only the optically active (+) biotin is biologically active, the racemic biotin thus produced must then still be separated into the optical enantiomers. On the one hand, in this case all reaction steps are performed with racemic materials, as a result of which the doubled amounts of substance must be processed. On the other hand, resolution of the racemic biotin into the corresponding enantiomers is a very complicated process, which in addition is also unprofitable, since the undesirable enantiomer practically no longer racemizes and can no longer be fed back into the process.
An improvement of such process is known from U.S. Pat. No. 2,489,235. In this case, the resolution of the racemates is already performed in an earlier step, but still this process has the drawback that most of the reaction steps are performed with racemic material and here too the undesirable enantiomer resulting from this resolution practically no longer racemizes and can no longer be fed back to the process.
M. Murakami et al. have developed an improved product for the production of dl-biotin (see Japanese Published Patent Document Nos. 31,669/1970, 37,775/1970, 37,776/1970 and 3,580/1971). The improvement consists in introducing a carboxybutyl group in the 4 position of the dl-1,3-dibenzylhexahydrothieno [3,4-d]-imidazol2,4-dione. This dione is reacted with a 1,4-dihalomagnesium butane and then carboxylated with carbon dioxide.
Gerecke et al. German Pat. No. 2,058,248, have developed a further improvement, by already producing--in an earlier step by optical resolution of a triethylamine salt of the following formula, in which R represents a cholesteryl radical, or of an ephedrine salt of the following formula, in which R represents a cyclohexyl radical: ##STR4## and by further conversion with alkali metal boron hydrides--an optically active lactone of the formula: ##STR5## is produced as an optically active intermediate product.
A significant drawback for an industrial use consists in the use of the expensive optically active compounds chloresterol and ephedrine as well as expensive alkali metal boron hydrides. The processes of European Published Application Nos. 0161580 and 0173185 are tainted with the same drawback, namely, the use of expensive optically active compounds.
Moreover, it is known from European Published Application No. 0154225 to produce biotin from 1,3-benzylhexahydro-1H-thienoimidazoldiones by a special Grignard reaction with a trioxaadamantylbutylmagnesium bromide, a subsequent dehydration and by cleavage of the corresponding protective groups. This process is just as unfavorable for an industrial process especially because of its expensive Grignard compounds.